Although inflammation is central to periodontal diseases (PD), the role(s) of neutrophil (PMN)-derived lipid mediators (LM) have yet to be clarified. Adult periodontitis (AP) and local juvenile periodontitis (LJP) are exacerbated by hot PMN-derived pro-inflammatory molecules that can affect integrity of the periodontium and may serve as "red flags" for later systemic events such as heart disease. We are accustomed to thinking about these diseases as reflective of a micro-environmental excess of "pro-inflammatory molecules" liberated by host-bacterial interactions, while it is also possible that similar disease states can arise from a loss of host by host-bacterial interactions, while it is also possible that similar disease states can arise from a loss of host "down-regulatory circuits". Recently, we identified both novel intracellular (polyisoprenyl phosphates: PIPP) and extracellular (aspirin-triggered 15-epi-lipoxins) mediators and their protein targets that regulate PMN-mediated inflammation. Since PMN recruitment and inappropriate release of their degradative agents are important in PD, we propose the following hypotheses: In healthy (non-PD) individuals, lipoxins (LX) and 15- epi- LX interact with PMN receptors to remodel polyisoprenyl phosphates that function together as "endogenous anti-inflammatory circuits" to prevent overt PMN responses and protect the periodontium; this mechanism for damping local inflammation is diminished in patients with PD. To address this, Project #1 of this program project proposes the following specific aims. In Aim 1 we will focus on establishing the role of PMN cyclooxygenase-2 and its impact in PMN lipid mediator profiles form AP and LJP patients; Aim 2 will determine the basis for LM regulation of AP & LJP PMN responses. In work in progress, we found that LJP PMN generate enhanced levels of LX, but are "hyporesponsive" to LX regulation. A multi-pronged approach is taken to determine structure- function relationships and the cellular level of the LJP defect. Experiments in Aim 3 will address the role of polyisoprenyl phosphate signaling in PMN and PD PMN by establishing new techniques to monitor remodeling of these novel signals and their role in LT and LX actions. Experiments in techniques to monitor remodeling of these novel signals and their role in LT and LX actions. Experiments in techniques to monitor remodeling of these novel signals and their role in LT and LX actions. Experiments in Aim 4 will document novel LM in crevicular fluids and their relationship to LM generated by PD PMN from the same patient. The impact of treatment on the profile of "anti-inflammatory" LM will be determined. The long-term goals of Project #1 are two fold: 1) to provide the groundwork for therapeutic targeting of these long-term goals of Project #1 are two-fold: 1) to provide the groundwork for therapeutic targeting of these long-term goals of Project #1 are two-fold: 1) to provide the groundwork for therapeutic targeting of these novel "anti- inflammatory" LM circuits; and 2) to elucidate the contribution of novel LM to host mechanisms in PD.